This invention relates to metalloporphyrins such as metalloprotoporphyrins and metallomesoporphyrins, to therapeutically useful oral compositions containing these compounds together with a pharmaceutically acceptable carrier, and to the use of these compounds and compositions in treating various afflictions of animals, particularly mammals, and especially humans.
Heme is a red pigment comprised of four subunits called pyrroles; these subunits are chemically joined to form a single large tetrapyrrole (porphyrin) ring structure. A metal atom is chelated at the center of this porphyrin. In higher organisms this metal is iron and the porphyrin ring structure is called protoporphyrin IX.
In mammals and other vertebrates protoporphyrin IX, hereinafter heme is enzymatically degraded to form open chain tetrapyrroles generally called bile pigments (e.g., bilirubin, biliverdin) and iron. Heme oxygenase is the rate-limiting enzyme in the catabolism of heme to bile pigments and iron. This degradation takes place in certain organs of animals. For example, in the liver with respect to the degradation of heme from hemoglobin and other heme proteins. In the digestive system, by the action of heme oxygenase in the small intestinal epithelium, heme from foodstuffs is degraded to bile pigments and iron. The iron is then absorbed by the animal. This may result in excess iron accumulation in the body which can cause deleterious and even lethal consequences.
A chronic excess of iron may derive from several sources, e.g., cooking methods (iron pots) or directly via the diet (e.g., iron-overload induced cutaneous porphyrin), from excess therapeutic administration of the metal in an attempt to vigorously treat unresponsive anemias; from hypertransfusions to which certain patients with blood disorders are subject; idiopathically from the disorders collectively known as "hemachromatosis"; from certain industrial exposures; but the most common causes of excess iron deposition in tissues, and the resultant pathologic consequences which derive thereof, are a consequence of common congenital hemolytic anemias such as sickle cell disease, the various forms of thalassemia, G-6-PD deficiency, hereditary spherocytosis and the like. In these disorders, a greatly shortened red cell life span results in continuous large depositions of iron in tissues to an extent exceeding the capacity of the body to re-utilize the metal. Thus tissue concentrations of iron rise to very high, toxic levels and lead to impairment of vital organ functions manifest for example by cardiomyopathy, pancreatic insufficiency (diabetes) and generalized endocrine failure.
A principal cause of abnormal iron is the iron in foodstuffs, particularly those of animal origin. This invention is particularly useful in neutralizing this potential source of excessive iron.
There is no physiological mechanism for excreting this excess of iron and the only generally available therapeutic modality for this purpose is a pharmacological agent known as desferrioxamine. This agent is not specific for iron however and chelates other metals as well; it must in order to be reasonably effective be given intramuscularly and causes substantial local inflammation at the site of injection. Further, original suggestions that it was non-toxic have proved incorrect and a large number of toxic reactions in treated patients have now been reported to occur after its use, including hypotension and allergic reactions.
For animals suffering from a chronic excess of iron, regardless of the source of this condition, it is desirable to have available methods and materials to inhibit the catabolism of heme from foodstuffs in the small intestine so that the absorption of iron compounds from foodstuffs is prevented. In particular, an oral composition for preventing the catabolism by intestinal heme oxygenase of heme from foodstuffs and the concommitant absorption of iron compounds from said foodstuffs is needed, especially or individuals suffering from a chronic excess of iron, regardless of the source of this condition.
Sn-protoporphyrin (SnPP) as described in copending and commonly assigned U.S. patent application Ser. No. 07/325,086, filed Mar. 16, 1989, manifests the extremely advantageous property of greatly enhancing the biliary excretion of iron into the intestinal contents where the metal is eliminated. Sn-PP is administered parenterally and acts in this additional fashion by blocking the binding of heme to heme oxygenase, thus preventing the release of iron which normally occurs in the process of heme catabolism and allowing one atom of iron to be excreted into the intestine with every molecule of uncatabolized heme.
In commonly assigned U.S. Pat. No. 4,657,902, Sn-mesoporphyrin (Sn-MP) is employed parenterally in the treatment of mammals, including humans, in need of such treatment, to increase the rate at which heme is excreted, to decrease the rate of heme metabolism, and to control the rate of tryptophan metabolism in the liver.
Commonly assigned U.S. Pat. No. 4,619,923 concerns a method of increasing the rate of tryptophan metabolism in the liver of humans in need of such increase through the parenteral administration of an effective amount of tin. In addition, commonly assigned U.S. Pat. No. 4,782,049 relates to the parenteral administration of SnPP and SnMP together with ultraviolet light in the treatment of psoriasis.
Commonly assigned U.S. Pat. No. 4,684,637 relates to preventing hyperbilirubinemia in mammals by decreasing the rate of heme metabolism through parenteral administration of tin protoporphyrin and chromium protoporphyrin.
All of these patents refer to parenteral administration. So far as is known, there has not, heretofore, been any teaching or suggestion of administering these products orally for any purpose. Heretofore there has been no proposal to employ metalloporphyrins or oral compositions containing these compounds for inhibiting the activity of intestinal heme oxygenase and thereby reducing the absorption of iron from foodstuffs by animals in need of such prevention. Moreover, heretofore it was believed that there is no inhibition of intestinal heme oxygenase either in vitro or in vivo after administration of SnPP (See Hintz et al, Ped. Res. 23: 50-53 (1988)).